We discovered that the SET oncoprotein is overexpressed in 90% of biopsy samples from patients with hematological cancers and about 50% of biopsy samples from patients with solid tumors (Vitek et al. US Patent 8,623,601, and 7, 9, 10, 12). Also known as I2PP2A, one of SET's normal functions is to inhibit Protein Phosphatase 2A (PP2A) (2). Hahn showed that cancerous transformation of human cells required inhibition of PP2A (3). Of the known PP2A-inhibitors, only SET has been reported to be druggable (2, 4). We discovered that apolipoprotein-E (apoE) and the apoE-mimetic peptide spanning residues 133-149 specifically bound SET (2, Fig. 3). Upon binding of apoE-133-149 to SET, cellular PP2A activity levels increased supporting that apoE-133-149 is a SET antagonist (2, Fig. 2 & 4). But most importantly, the SET antagonist known as OP449 is also an apoE-peptide-mimetic that kills human cancer cells in vitro and in xenografted orthotopic tumors from both hematological and solid tumors (4, 5, 6, 7, 8, 9, 10, 11, 12, 13). Together, these data strongly support that antagonism of SET is a useful target for anti-cancer, targeted drug development. Since OP449 is an injectable peptide, we propose a 4-step screening cascade (Figure 1) to find orally- active small-molecule antagonists of SET that will permit re-activation f PP2A and the death of cancer cells. In this Phase 1 grant, we will initiate Steps 1 & 2 of screening cascade. We seek support in this proposal to use our High Throughput Screen (HTS) to find small-molecule SET binders. Hits from this HTS assay will then be subjected to an orthogonal assay where the toxicity of each hit to a cancer cell line and to a normal cell line wil be evaluated. Additional orthogonal assays to further confirm the usefulness of hit compounds will be pursued in future applications. Similar screens to find small molecules that disrupt protein-protein-interactions (PPIs) have, for example, yielded several small molecules (21, 22) including Nutlin-3a (18), which disrupts p53:MDM2 binding. The MDM2-disruptor AMG232 is about to start, and Nutlin-3 (RG7112) is currently in clinical trials, where it has shown anti-cancer activity in patients (18, 19).